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Single Molecule Fluorescence Energy Transfer Study of Ribosome Protein Synthesis
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Stochastic gating and drug-ribosome interactions

Andrea C Vaiana1, Kevin Y Sanbonmatsu

  • 1Theoretical Division, Los Alamos National Laboratory, Mail Stop K710, T-10, Los Alamos, NM 87545, USA.

Journal of Molecular Biology
|January 17, 2009
PubMed

Insights

Gentamicin antibiotic action involves rapid ribosome decoding base flipping, preceding drug binding. This supports a stochastic gating mechanism, not induced fit, revealing complex drug-ribosome interactions.

Area of Science:

  • Molecular Biology
  • Computational Chemistry
  • Pharmacology

Background:

  • Gentamicin is a critical antibiotic for treating infections like anthrax and MRSA.
  • Its mechanism involves disrupting bacterial ribosome function during mRNA decoding.
  • Understanding the precise dynamics of gentamicin-ribosome interaction is key to antibiotic efficacy.

Purpose of the Study:

  • To investigate the thermodynamics of the ribosomal decoding site.
  • To elucidate the binding mechanism of gentamicin to the ribosome.
  • To explore the free-energy landscape of drug-ribosome interactions.

Main Methods:

  • Explicit solvent all-atom molecular simulation.
  • Replica exchange molecular dynamics (REMD) simulations with 15 μs aggregate sampling.
  • Free-energy landscape calculations, including enthalpic and entropic contributions.

Main Results:

  • Ribosomal decoding bases exhibit conformational flipping on a timescale faster than gentamicin binding.
  • This supports a stochastic gating mechanism for antibiotic binding.
  • Drug dissociation involves navigating multiple metastable states, not a simple bound/unbound model.

Conclusions:

  • Gentamicin binding to the ribosome follows a stochastic gating mechanism.
  • The dynamic nature of the decoding site influences antibiotic interaction.
  • Molecular simulations provide detailed insights into complex drug-ribosome thermodynamics.

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